Assessment and acceleration of binding energy calculations for protein–ligand complexes by the fragment molecular orbital method

Abstract

In the field of drug discovery, it is important to accurately predict the binding affinities between target proteins and drug applicant molecules. Many of the computational methods available for evaluating binding affinities have adopted molecular mechanics-based force fields, although they cannot fully describe protein-ligand interactions. A noteworthy computational method in development involves large-scale electronic structure calculations. Fragment molecular orbital (FMO) method, which is one of such large-scale calculation techniques, is applied in this study for calculating the binding energies between proteins and ligands. By testing the effects of specific FMO calculation conditions (including fragmentation size, basis sets, electron correlation, exchange-correlation functionals, and solvation effects) on the binding energies of the FK506-binding protein and 10 ligand complex molecule, we have found that the standard FMO calculation condition, FMO2-MP2/6-31G(d), is suitable for evaluating the protein-ligand interactions. The correlation coefficient between the binding energies calculated with this FMO calculation condition and experimental values is determined to be R = 0.77. Based on these results, we also propose a practical scheme for predicting binding affinities by combining the FMO method with the quantitative structure-activity relationship (QSAR) model. The results of this combined method can be directly compared with experimental binding affinities. The FMO and QSAR combined scheme shows a higher correlation with experimental data (R = 0.91). Furthermore, we propose an acceleration scheme for the binding energy calculations using a multilayer FMO method focusing on the protein-ligand interaction distance. Our acceleration scheme, which uses FMO2-HF/STO-3G:MP2/6-31G(d) at R(int) = 7.0 Å, reduces computational costs, while maintaining accuracy in the evaluation of binding energy.

The fragment molecular orbital method: theoretical development, implementation in GAMESS, and applications

“…In it, fragments are divided into layers, and each layer is allowed to have its own basis set and method. In a typical example, a protein–ligand binding site is described with a higher level than the rest of the protein . Although the formulation is general for multiple layers, so far at most two layers have been used.…”

A 3D-QSAR Analysis of CDK2 Inhibitors Using FMO Calculations and PLS Regression

“…Some previous studies combining FMO calculations and regression analysis have been reported, including a Linear Expression by Representative Energy Terms (LERE)-QSAR analysis by Chuman and colleagues, 8) a PLS regression of CDK2 inhibitors by Mazanetz et al 9) and a PLS regression of FK506-binding protein (FKBP) ligands by Otsuka et al 10) In all cases, the usefulness of the FMO method and regression analysis was demonstrated. However, in these studies, the interaction/binding energy between the whole protein and a single ligand was used as a descriptor, and individual energy information about the amino acid residue fragments was not used.…”

Theoretical Model of EphA2-Ephrin A1 Inhibition

“…Such an approach neglects, among other entropic contributions, the influence of solvation effects. To include the latter, one would need a much more time-consuming method, for instance free-energy perturbation (FEP), Molecular Mechanics/Poisson-Boltzmann, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA and MM/PBSA, respectively) [ 36 ] or Fragment Molecular Orbital (FMO) approach [ 37 ]. The quantum chemical methods (like DFT or MP2) are rather not combined with empirical solvation or ligand entropy estimates [ 36 ], and therefore they should work only if the neglected contributions to the energy of binding are similar within the studied set of complexes.…”